Premature ageing in mice expressing defective mitochondrial DNA polymerase

Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.     

Early human use of marine resources and pigment in South Africa during the Middle Pleistocene

Genetic and anatomical evidence suggests that Homo sapiens arose in Africa between 200 and 100 thousand years (kyr) ago, and recent evidence indicates symbolic behaviour may have appeared approximately 135-75 kyr ago. From 195-130 kyr ago, the world was in a fluctuating but predominantly glacial stage (marine isotope stage MIS6); much of Africa was cooler and drier, and dated archaeological sites are rare. Here we show that by approximately 164 kyr ago (+/-12 kyr) at Pinnacle Point (on the south coast of South Africa) humans expanded their diet to include marine resources, perhaps as a response to these harsh environmental conditions. The earliest previous evidence for human use of marine resources and coastal habitats was dated to approximately 125 kyr ago. Coincident with this diet and habitat expansion is an early use and modification of pigment, probably for symbolic behaviour, as well as the production of bladelet stone tool technology, previously dated to post-70 kyr ago. Shellfish may have been crucial to the survival of these early humans as they expanded their home ranges to include coastlines and followed the shifting position of the coast when sea level fluctuated over the length of MIS6.     

NOD-like receptors: Ancient sentinels of the innate immune system

NOD-like receptors (NLRs) comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. Genetic variants in NLR genes have been associated with complex chronic inflammatory barrier diseases (e.g. Crohn disease, bronchial asthma). In this review, we focus on the molecular pathophysiology of NLRs in the context of chronic inflammatory diseases and pinpoint recent advances in the evolutionary understanding of NLR biology. We propose that the field of NLRs may serve as a prototype for how a comprehensive understanding of an element of the immunological barrier will eventually lead to the development of targeted diagnostic, therapeutic and/or preventive strategies. Received 29 October 2007; received after revision 10 December 2007; accepted 19 December 2007     

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10?12) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10?11) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10??) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10?11) and a tag SNP for NAT2 acetylation status (P = 4 × 10?11), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.     

Competition and niche partitioning among Pseudoroegneria spicata, Hedysarum boreale , and Centaurea maculosa

Maximizing desired plant diversity has been suggested as a means of minimizing non-indigenous plant invasion on rangeland by maximizing niche occupation. Competition between 2 desired indigenous species, Pseudoroegneria spicata (Pursh). L?ve (bluebunch wheatgrass) and Hedysarum boreale Nutt. var. boreale (northern sweetvetch), and a non-indigenous invader, Centaurea maculosa Lam. (spotted knapweed), was quantified using growth of isolated individuals and 2 three-species addition series experiments. Seeding densities of P. spicata remained constant at 0, 200, 400, and 800 seeds m -2 in both experiments. H. boreale and C. maculosa seeding densities were 0, 200, 400, and 800 seeds m -2 , respectively, in the 1st experiment and 0, 400, 800, and 1600 seeds m -2 , respectively, in the 2nd experiment. Densities were factorially arranged. Pots were place in an environmental chamber (12 C, 12-h day length, 200 μmol photons m -2 s -1 spectral light) in a randomized-complete-block design. After 90 d the growth rate of P. spicata (92.1 mg d -1 shoot growth) was greater than that of the 2 forbs (1.6 and 5.5 mg d -1 for H. boreale and C. maculosa , respectively), and growth rates of the 2 forbs were similar to one another. Curvilinear regression indicated that intraspecific competition was more important in determining shoot weight than intraspecific competition. In addition, the 2 forbs competed more directly with each other than with P. spicata . Competition coefficient ratios (1.42 and 1.53 for P. spicata with H. boreale and C. maculosa , respectively, and 1.03 for H. boreale with C. maculosa ) indicated substantial partitioning of resources between P. spicata and each of the forbs. Little or no resource partitioning occurred between forbs. This study suggests that increasing desired plant diversity may minimize weed invasion by increasing niche occupation.     

Retinal receptors in rodents maximally sensitive to ultraviolet light

High sensitivity to near-ultraviolet light is a fundamental feature of vision in many invertebrates. Among vertebrates there are some amphibians, birds and fishes that are also sensitive to near-ultraviolet wavelengths. This sensitivity can be achieved through a class of cone photoreceptor containing an ultraviolet-sensitive pigment. Although these receptors were thought not to exist in the eyes of mammals, we now report that some rodents have a retinal mechanism that is maximally sensitive to ultraviolet light.     

Cone monochromacy and a reversed Purkinje shift in the gerbil

Summary Retinal spectral sensitivity of the gerbil (Meriones unguiculatus) shows that this animal has a unique photoreceptor complement: there is only a single class of cone and the spectrum for these receptors is peak shifted toward the short wavelengths relative to the spectra obtained from rods.